Spinalmuscularatrophy(SMA)isaneurodegenerativediseasecharacterizedbymotorneuronlossandskeletal muscleatrophy.SMAiscausedbyubiquitousdeficiencyintheSMNproteinandistheleadinggeneticcauseof infantmortality.Todate,mostSMAtherapeuticapproacheshavefocusedonincreasingSMNexpressionand SMN-inducingtherapieshaverecentlybeenapprovedforSMA.However,thesetherapiesalonedonotprovide acure orSMA ndnotallpatientsrespond totreatment.Therefore,it remains essentialtounderstand the underlyingmechanismsofSMAand identifySMN-independent therapeuticapproaches thatcanenhancethe benefitofSMN-inducingstrategiesthroughcombinatorial treatment.Inthis context,motorneurondeath isan irreversible pathogenichallmarkofSMA.Therefore,preventingmotorneurondegeneration has fundamental clinicalimplicationsforSMAtherapyandcouldextendthewindowofopportunityforSMN-inducingtherapiesto exert their effect.However,thisishinderedby limited knowledge ofthedeath pathway and availabilityof druggable-targetsforhaltingthisprocess.Thisprojectaimstoaddresstheseoutstandingissuesbyinvestigating themechanismsunderlyingtheinitiationandexecutionofmotorneurondegenerationinSMAaswellasvalidate thetherapeuticpotentialof pharmacologicallytargetingthispathway in mousemodels of the disease.The premiseofourproposedworkisthattheneurodegenerativepathwayofSMAmotorneuronsrepresentsatarget- richdomainforthediscoveryofdisease-modifyingpharmacologicalapproachesthatareSMN-independentand suitedforcombinatorialtreatmentofSMA.Buildingonourpublishedandpreliminarystudies,wewillcharacterize theupstream mechanismsdrivingmotorneuron death inSMAbased onourhypothesis thatSMN deficiency triggersap38MAPK/p53-dependentneurodegenerativepathway (Aim1).To broaden the range of candidate targetsfordevelopingSMN-independentneuroprotectiveapproachesforSMA,wewilldeterminetheexecution mechanismsofmotorneurondeaththroughtheidentificationandfunctionalcharacterizationofthedownstream effectorsofp53-dependent neurodegenerationinSMA(Aim2).Lastly, we willleverageon theavailabilityof a highlyselective,brainpermeableinhibitortotestthehypothesisthatp38MAPKactivationisasharedpathogenic mechanism associated with motor neuron death across mouse modelsofSMAwithvaryingdiseaseseverity whose inhibition is a viable therapeutic approach (Aim 3).Wewillalsoevaluatewhether pharmacological inhibitionofp38MAPKenablesenhancedsynapticrewiringbypreservingSMAmotorneuronsinaparadigmof combinatorialtreatmentwithSMNupregulation.Successfulaccomplishmentofourobjectiveshasthepotential toprovidekey insights intothe mechanismsofmotorneurondeath inSMA, identifynewdiseasemarkersand candidate targets tohalttheneurodegenerativeprocess,andestablishpharmacologicalapproachesfor neuroprotectiontobeusedincombinatorialtreatmentofthediseasewithSMN-inducingtherapies.